Adenanthin targets peroxiredoxin I and II to induce differentiation of leukemic cells

Area of Science:

• Biochemistry
• Pharmacology
• Oncology

Background:

• Peroxiredoxins (Prxs) are crucial enzymes implicated in major diseases, including cancers.
• Development of isotype-specific Prx inhibitors is essential for targeted therapies.
• Acute promyelocytic leukemia (APL) is a significant hematological malignancy.

Purpose of the Study:

• To investigate adenanthin, a natural diterpenoid, as a potential therapeutic agent for APL.
• To elucidate the mechanism of action of adenanthin in inducing APL cell differentiation.
• To evaluate the efficacy of adenanthin in preclinical APL models.

Main Methods:

• Isolation and characterization of adenanthin from Rabdosia adenantha leaves.
• In vitro assays to assess adenanthin's inhibitory effects on Prx I and Prx II peroxidase activities.
• Cellular assays to measure reactive oxygen species (ROS) levels, kinase activation, and gene expression.
• In vivo studies using mouse models of APL to evaluate tumor growth and survival.

Main Results:

• Adenanthin directly targets and inhibits the peroxidase activity of Prx I and Prx II by binding to their resolving cysteines.
• Treatment with adenanthin leads to elevated intracellular hydrogen peroxide (H(2)O(2)) levels.
• Adenanthin activates extracellular signal-regulated kinases (ERK) and upregulates CCAAT/enhancer-binding protein β (C/EBPβ), promoting APL cell differentiation.
• Adenanthin demonstrates efficacy in repressing tumor growth and prolonging survival in both retinoic acid-sensitive and -resistant mouse APL models.

Conclusions:

• Adenanthin is identified as the first natural compound lead for developing Prx I- and Prx II-targeted therapeutic agents.
• Adenanthin-induced differentiation represents a promising therapeutic approach for APL.
• Targeting Prx I and Prx II with adenanthin offers a novel strategy for APL treatment, overcoming retinoic acid resistance.